microglia

Call it Mighty Mouse: Breakthrough leaps Alzheimer's research hurdle

Study reveals crucial mechanisms contributing to the disease

July 31, 2019

Science Daily/University of California - Irvine

University of California, Irvine researchers have made it possible to learn how key human brain cells respond to Alzheimer's, vaulting a major obstacle in the quest to understand and one day vanquish it. By developing a way for human brain immune cells known as microglia to grow and function in mice, scientists now have an unprecedented view of crucial mechanisms contributing to the disease.

 

The team, led by Mathew Blurton-Jones, associate professor of neurobiology & behavior, said the breakthrough also holds promise for investigating many other neurological conditions such as Parkinson's, traumatic brain injury, and stroke. The details of their study have just been published in the journal Neuron.

 

The scientists dedicated four years to devising the new rodent model, which is considered "chimeric." The word, stemming from the mythical Greek monster Chimera that was part goat, lion and serpent, describes an organism containing at least two different sets of DNA.

 

To create the specialized mouse, the team generated induced pluripotent stem cells, or iPSCs, using cells donated by adult patients. Once created, iPSCs can be turned into any other type of cell. In this case, the researchers coaxed the iPSCs into becoming young microglia and implanted them into genetically-modified mice. Examining the rodents several months later, the scientists found about 80-percent of the microglia in their brains was human, opening the door for an array of new research.

 

"Microglia are now seen as having a crucial role in the development and progression of Alzheimer's," said Blurton-Jones. "The functions of our cells are influenced by which genes are turned on or off. Recent research has identified over 40 different genes with links to Alzheimer's and the majority of these are switched on in microglia. However, so far we've only been able to study human microglia at the end stage of Alzheimer's in post-mortem tissues or in petri dishes."

 

In verifying the chimeric model's effectiveness for these investigations, the team checked how its human microglia reacted to amyloid plaques, protein fragments in the brain that accumulate in people with Alzheimer's. They indeed imitated the expected response by migrating toward the amyloid plaques and surrounding them.

 

"The human microglia also showed significant genetic differences from the rodent version in their response to the plaques, demonstrating how important it is to study the human form of these cells," Blurton-Jones said.

 

"This specialized mouse will allow researchers to better mimic the human condition during different phases of Alzheimer's while performing properly-controlled experiments," said Jonathan Hasselmann, one of the two neurobiology & behavior graduate students involved in the study. Understanding the stages of the disease, which according to the Alzheimer's Association can last from two to 20 years, has been among the challenges facing researchers.

 

Neurobiology & behavior graduate student and study co-author Morgan Coburn said: "In addition to yielding vital information about Alzheimer's, this new chimeric rodent model can show us the role of these important immune cells in brain development and a wide range of neurological disorders."

https://www.sciencedaily.com/releases/2019/07/190731125448.htm

Raising eyebrows on neuroinflammation: Study finds novel role for 'skin plumping' molecule

Neuroscientists identify surprising brain action of cartilage component hyaluronic acid

July 11, 2019

Science Daily/Florida Atlantic University

Scientists have discovered a novel mechanism and role in the brain for hyaluronic acid -- a clear, gooey substance popularized by cosmetic and skin care products. Hyaluronic acid may be the key in how an immune signal moves from the blood stream to the brain, activating the brain's resident immune cells, the microglia. Findings from this study have important implications for better treatments for stroke, neurodegenerative diseases, as well as head injuries.

 

This clear, gooey substance, which is naturally produced by the human body, has been popularized by cosmetic and skin care products that promote healthier, plumper and more supple skin. Also recognized for its abilities to speed up wound healing, reduce joint pain from osteoarthritis, and relieve dry eye and discomfort, a neuroscientist at Florida Atlantic University's Brain Institute (I-BRAIN) and Schmidt College of Medicine, has discovered a novel mechanism and role in the brain for hyaluronic acid.

 

In a study published in the journal Brain, Behavior and Immunity, Ning Quan, Ph.D., lead author, a professor of biomedical science in FAU's Schmidt College of Medicine and a member of I-BRAIN, and collaborators, have discovered that hyaluronic acid may be the key in how an immune signal moves from the blood stream to the brain, activating the brain's resident immune cells, the microglia.

 

This unsuspected molecule may be the main signal passed between these cells, and this new discovery could lead to novel opportunities to shut down brain inflammatory responses. Findings from this study have important implications for better treatments for stroke, neurodegenerative diseases, as well as head injuries.

 

"We normally think of hyaluronic acid with respect to cartilage formation and also for its role in many processes including cancer progression and metastasis," said Quan. "However, what we have uncovered in our study is a completely unique role for this molecule. We have been able to document a connection between the blood cells and the brain cells, showing that the activating signal passed between these cells is hyaluronic acid."

 

Quan and collaborators from the Sichuan University, The Ohio State University, and the University of Illinois Urbana-Champaign, demonstrate that inflammation in the central nervous system is oftentimes quenched or restricted, as neurons are extremely vulnerable to inflammation-caused damages. However, this inflammation can be aberrantly amplified through endothelial cell-microglia crosstalk when the brain constantly receives inflammatory signals. Quan's work identified hyaluronic acid as the key signal released by endothelial cells to stimulate microglia and promote oxidative damage.

 

"To prevent the inflammation from being intensified in the brain, you have to stop the communication between the two cell types," said Xiaoyu Liu, Ph.D., another corresponding author of the study in FAU's Schmidt College of Medicine and I-BRAIN. "We found ascorbyl palmitate, also known as 'Vitamin C Ester,' to be quite effective in inhibiting microglia and reducing the production of inflammatory hyaluronic acid."

 

In the past, Vitamin C Ester has been widely used as a source of vitamin C and an antioxidant food additive. Now, this latest discovery suggests a novel function of Vitamin C Ester: treating central nervous system inflammation.

 

"As the newest addition to our Department of Biomedical Science, Dr. Quan's work already is making an important impact on our mission to advance understanding of human health and disease," said Janet Robishaw, Ph.D., senior associate dean for research and chair of the Department of Biomedical Science in FAU's Schmidt College of Medicine. "Long known as a popular skin and joint supplement, this discovery identifies a novel role for hyaluronic acid to potentially treat conditions caused by inflammation in the central nervous system."

 

Inflammation can occur in the central nervous system as a result of head trauma or stroke, or as part of a systemic immune response. Inflammation within the central nervous system has been associated with chronic neurodegenerative diseases including Alzheimer's disease, Parkinson's disease and multiple sclerosis.

 

"Neurological disorders such as Parkinson's disease and Alzheimer's disease impact all races, genders, and geographical backgrounds," said Randy Blakely, Ph.D., executive director of FAU's I-BRAIN. "Findings from this study may thus have global implications for how we treat neurodegeneration arising from traumatic brain injuries and brain changes associated with aging and dementia. This exceptional research by Dr. Quan and his colleagues is a testament to the cutting-edge work that is being conducted by our Brain Institute members and the research faculty in FAU's Schmidt College of Medicine."

https://www.sciencedaily.com/releases/2019/07/190711141439.htm

Native California medicinal plant may hold promise for treating Alzheimer's

Salk scientists identify possible healing compound in Yerba santa

February 20, 2019

Science Daily/Salk Institute

The medicinal powers of aspirin, digitalis, and the anti-malarial artemisinin all come from plants. A discovery of a potent neuroprotective and anti-inflammatory chemical in a native California shrub may lead to a treatment for Alzheimer's disease based on a compound found in nature.

 

"Alzheimer's disease is a leading cause of death in the United States," says Senior Staff Scientist Pamela Maher, a member of Salk's Cellular Neurobiology Laboratory, run by Professor David Schubert. "And because age is a major risk factor, researchers are looking at ways to counter aging's effects on the brain. Our identification of sterubin as a potent neuroprotective component of a native California plant called Yerba santa (Eriodictyon californicum) is a promising step in that direction."

 

Native California tribes, which dubbed the plant "holy herb" in Spanish, have long used Yerba santa for its medicinal properties. Devotees brew its leaves to treat respiratory ailments, fever and headaches; and mash it into a poultice for wounds, sore muscles and rheumatism.

 

To identify natural compounds that might reverse neurological disease symptoms, Maher applied a screening technique used in drug discovery to a commercial library of 400 plant extracts with known pharmacological properties. The lab had previously used this approach to identify other chemicals (called flavonoids) from plants that have anti-inflammatory and neuroprotective properties.

 

Through the screen, the lab identified a molecule called sterubin as Yerba santa's most active component. The researchers tested sterubin and other plant extracts for their impact on energy depletion in mouse nerve cells, as well as other age-associated neurotoxicity and survival pathways directly related to the reduced energy metabolism, accumulation of misfolded, aggregated proteins and inflammation seen in Alzheimer's. Sterubin had a potent anti-inflammatory impact on brain cells known as microglia. It was also an effective iron remover -- potentially beneficial because iron can contribute to nerve cell damage in aging and neurodegenerative diseases. Overall, the compound was effective against multiple inducers of cell death in the nerve cells, according to Maher.

 

"This is a compound that was known but ignored," Maher says. "Not only did sterubin turn out to be much more active than the other flavonoids in Yerba santa in our assays, it appears as good as, if not better than, other flavonoids we have studied."

 

Next, the lab plans to test sterubin in an animal model of Alzheimer's, then determine its drug-like characteristics and toxicity levels in animals. With that data, Maher says, it might be possible to test the compound in humans, although it would be critical to use sterubin derived from plants grown under standardized, controlled conditions. She says the team will likely generate synthetic derivatives of sterubin.

https://www.sciencedaily.com/releases/2019/02/190220174105.htm

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